Hematopoietic stem cells (HSC) are pluripotent and ultimately gives rise to all types of terminally differentiated blood cells. HSC can self-renew or differentiate into more committed hematopoietic progenitor cells (HPC), which progenitor cells are irreversibly determined to be ancestors of only a few types of blood cell. For instance, HSC can differentiate into (i) myeloid progenitor cells, which myeloid progenitor cells ultimately give rise to monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells, or (ii) lymphoid progenitor cells, which lymphoid progenitor cells ultimately give rise to T-cells, B-cells, and lymphocyte-like cells called natural killer cells (NK-cells). Once the HSC differentiate into a myeloid progenitor cell, its progeny cannot give rise to cells of the lymphoid lineage, and, lymphoid cells cannot give rise to cells of the myeloid lineage. For a general discussion of hematopoiesis and HSC differentiation, see Chapter 17, Differentiated Cells and the Maintenance of Tissues, Alberts et al., 1989, Molecular Biology of the Cell, 2nd Ed., Garland Publishing, New York, N.Y.; Chapter 2 of Regenerative Medicine, Department of Health and Human Services, Aug. 5, 2006, and Chapter 5 of Hematopoietic Stem Cells, 2009, Stem Cell Information, Department of Health and Human Services. Precursor cells can include HSC, HPC and/or mixtures of HSC and HPC.
Precursor cell transplantation represents an important therapy due to these cell's capacity to restore blood and immune cells in transplant recipients. For example, transplantation of precursor cells can be used to treat subjects with inherited immuno-deficient or autoimmune diseases and diverse hematopoietic disorders. Precursor cell transplantation can also be used to treat chemotherapy and radiation-treatment patients because prolonged neutropenia and pancytopenia is common following these treatment regimens. As one example, and of particular concern, chemotherapeutic treatments for AML result in prolonged periods of profound neutropenia with infectious complications still common even in the setting of modern antimicrobial therapies with mortality rates as high as 20% in adolescent and young adults. Human bone marrow transplantation methods are also currently used as therapies for leukemia, lymphoma, and other life-threatening diseases.
In transplantation, it has been observed that patients receiving greater numbers of expanded precursor cells have more rapid recovery of their neutrophils following transplantation. Accordingly, high doses of precursor cells are needed to achieve rapid and sustained engraftment that is critical for a patient's survival and recovery. These findings suggest a critical need for generating greater numbers of precursor cells that reliably enhance neutrophil recovery.
Although progress toward efficient ex vivo expansion of precursor cells has been made, significant improvements in the efficacy and reproducibility of this technology are needed before it can be widely used. Accordingly, new approaches are needed.